There has been much emphasis in the pharmaceutical industry on the development of extended or controlled release drugs of various kinds. Doing so permits greater time periods between dosages, greater patient compliance, and the like. In connection with various water-soluble active ingredients, however, the development of extended release drug formulations has been somewhat difficult. This is exacerbated by the ready dissolution of these drugs, thus making it far more difficult to control the release of these substances for administration in a smaller number of dosages, such as single daily doses or even greater time periods between dosages.
Among these water-soluble drugs one highly important such drug is levetiracetam.
Levetiracetam or (S)-(−)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide, a laevorotatory compound, is disclosed as a protective agent for the treatment and the prevention of hypoxic and ischemic type aggressions of the central nervous system in European patent No. EP 0 162 036 B and has the following formula:

This compound is also effective in the treatment of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-(+)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide completely lacks activity (A. J. Gower et al., Eur. J. Pharmacol., 222, 1992, 193-203).
Recent developments in the production of extended release tablets of such drugs include U.S. Patent Publication Nos. 2007/0092569 (“the '569 Publication”); 2006/0165796 (“the '796 Publication”); 2008/0014271 (“the '271 Publication”); and 2008/0014264 (“the '264 Publication”). Each of these publications is generally directed to extended release formulations of levetiracetam in which a tablet core is prepared which primarily comprises a water-soluble rate-controlling polymer, optionally including conventional excipients, binders and the like. These hydrophilic rate-controlling polymers are included in the core in amounts from about 1% w/w to about 50% w/w. It is further disclosed that these tablets can be coated with a hydrophobic water-insoluble polymer either alone or including a water-soluble polymer as a nonfunctional coating.
Similarly, the '271 Publication discloses another such extended release composition. In this case, the tablet core containing levetiracetam includes a hydrophilic matrix agent or water-soluble agent, which can be combined with inert and lipophilic matrix agents, some of which can be water-nondispersible agents. In all of the compositions disclosed in the '271 Publication, however, the hydrophilic matrix agent is an essential element in the core including the water-soluble drug component levetiracetam.
Since these drug compositions require the use of a water-soluble polymer in the core to attempt to control the drug release rate, this results in a rather unpleasantly bulky drug product for high dose drugs such as levetiracetam, thus interfering with patient compliance. Furthermore, the flexibility of these extended release drugs is hampered with only a single drug release controlling mechanism in the core. In addition, with a highly swellable hydrophilic polymer matrix in these compositions, release controlling coatings on the systems are not extremely effective.
Additional efforts have therefore been made to provide novel and more patient-friendly extended release drug formulations including water-soluble drugs such as levetiracetam.